Background Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of ...the microbiota in the association between birth mode and atopic manifestations has not been studied yet. Objectives We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. Methods The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. Results Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. Conclusion Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations.
Background IL-1 receptor–like 1 (IL1RL1) is a membrane receptor involved in TH 2 inflammatory responses and eosinophilia. Single nucleotide polymorphisms (SNPs) in IL1RL1 have been associated with ...blood eosinophil counts in a genome-wide association study and with asthma in family-based and case-control studies. Objective We assessed in the prospective birth cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA) whether IL1RL1 SNPs associate with levels of its soluble transcript IL1RL1 (IL1RL1-a) in serum, blood eosinophil counts, and asthma prevalence from birth to age 8 years, and whether IL1RL1-a serum levels associate with blood eosinophil counts. Methods Fifteen IL1RL1 SNPs were genotyped. Serum IL1RL1-a levels were measured in 2 independent subsets within PIAMA, at 4 and 8 years. Blood eosinophil counts were measured in 4-year-old children. Results In 2 independent subsets of children, 13 of 15 SNPs were associated with serum IL1RL1-a levels at ages 4 and 8 years with a consistent direction of effect for each allele. Rs11685480 allele A and rs1420102 allele A were significantly associated with lower numbers of blood eosinophils. In the total cohort, rs1041973 allele A was associated with a decreased risk of developing asthma (odds ratio, 0.70; 95% CI, 0.54-0.90). Rs1420101, recently identified in a genome-wide association study in the Icelandic population, was not associated with asthma in this study. IL1RL1-a levels were not associated with eosinophil counts. Conclusion We demonstrate that IL1RL1 polymorphisms are associated with serum IL1RL1-a, blood eosinophils, and asthma in childhood.
Background Regulatory T–cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes ...involved in the development and function of regulatory T cells are associated with atopy and asthma development. Objective To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T–cell function— IL6 , IL6R , IL10 , heme-oxygenase 1 (HMOX1) , IL2 , Toll-like receptor 2 (TLR2) , TGFB1 , TGF-β receptor (TGFBR)–1 , TGFBR2 , IL2RA , and forkhead box protein 3 (FOXP3) —in relation to atopy and asthma. Methods Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by χ2 tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study). Results Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications. Conclusion Genes involved in the development and function of regulatory T cells, specifically IL2RA , TLR2 , TGFBR2 , and FOXP3 , associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma.
Background Perturbations in the gut microbiota have been linked to atopic diseases. However, the development of atopic diseases depends not only on environmental factors (like microbial stimulation) ...but also on genetic factors. It is likely that particularly gene-environmental interactions in early life determine the development of atopy. Objective We examine the interaction between detection of fecal Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations. Methods Within the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study, fecal samples of 957 one-month-old infants were collected and quantitatively screened for E coli . Fourteen haplotype-tagging polymorphisms in the genes TLR4 and CD14 were genotyped in 681 of the 957 children. Atopic outcomes were parentally reported eczema in the first 2 years of life and clinically diagnosed eczema and allergic sensitization at age 2 years. Multiple logistic regression was used to evaluate a multiplicative model of interaction. Results Most of the single nucleotide polymorphisms (SNPs) showed no significant interaction with E coli exposure for both eczema and allergic sensitization. A borderline significant multiplicative interaction was found between E coli and the rs2569190 (CD14/-159) SNP regarding allergic sensitization. Furthermore, a statistically significant multiplicative interaction was found for the TLR4 SNP rs10759932 ( P for interaction = .001). E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype (adjusted odds ratio, 0.31; 95% CI, 0.14-0.68) and not in children with the minor C allele. This interaction remained statistically significant after controlling for multiple testing. Conclusion The current study is the first to address the potential effect-modifying role of genetic variations in the relationship between the intestinal microbiota and allergy development.
Various forms of IL1RL1 can either stimulate or inhibit TH2 responses.3-6 Interestingly, single nucleotide polymorphisms (SNPs) located in the IL1RL1 gene are associated with atopic dermatitis.7 The ...adjacently located family members IL18R1 and IL18RAP may also be important in the development of asthma and atopy. Binding of IL-18 to IL-18R stimulates TH1 cytokine release, but also TH2-type cytokines, depending on its cytokine milieu.9 A recent publication showed strong associations with SNPs located in IL18R1 and asthma and atopic phenotypes.10 Our aim was to investigate whether SNPs in the IL1RL1 gene are associated with asthma, atopy, and allergic rhinitis.
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